The hypoxic tumor microenvironment and drug resistance against EGFR inhibitors: preclinical study in cetuximab-sensitive head and neck squamous cell carcinoma cell lines

BMC Research Notes

An Wouters²  Marc Baay²  Filip Lardon²  Marc Peeters¹  Ines De Pauw²  Jolien Van den Bossche²  Carolien Boeckx² 

[1] Department of Oncology, Antwerp University Hospital, Wilrijkstraat 10, Edegem, 2650, Belgium;Center for Oncological Research (CORE) Antwerp, University of Antwerp, Universiteitsplein 1, Wilrijk, 2610, Belgium

关键词: Cytotoxicity;    Hypoxia;    Erlotinib;    Cetuximab;   

Others  :  1232452
DOI  :  10.1186/s13104-015-1197-6

 received in 2014-11-13, accepted in 2015-05-20,  发布年份 2015

【 摘 要 】

Background

Increased expression of the epidermal growth factor receptor (EGFR) is observed in more than 90% of all head and neck squamous cell carcinomas (HNSCC). Therefore, EGFR has emerged as a promising therapeutic target. Nevertheless, drug resistance remains a major challenge and an important potential mechanism of drug resistance involves the hypoxic tumor microenvironment. Therefore, we investigated the cytotoxic effect of the EGFR-targeting agents cetuximab and erlotinib under normoxia versus hypoxia.

Findings

Three cetuximab-sensitive HNSCC cell lines (SC263, LICR-HN2 and LICR-HN5) were treated with either cetuximab or erlotinib. Cells were incubated under normal or reduced oxygen conditions (<0.1% O₂) for 24 or 72 h immediately after drug addition. Cell survival was assessed with the sulforhodamine B assay. Cetuximab and erlotinib established a dose-dependent growth inhibition under both normal and prolonged reduced oxygen conditions in all three HNSCC cell lines. However, a significantly increased sensitivity to cetuximab was observed in SC263 cells exposed to hypoxia for 72 h (p = 0.05), with IC₅₀ values of 2.38 ± 0.59 nM, 0.64 ± 0.38 nM, and 0.10 ± 0.05 nM under normoxia, hypoxia for 24 h and hypoxia for 72 h, respectively. LICR-HN5 cells showed an increased sensitivity towards erlotinib when cells were incubated under hypoxia for 24 h (p = 0.05).

Conclusions

Our results suggest that both EGFR-inhibitors cetuximab and erlotinib maintain their growth inhibitory effect under hypoxia. These results suggest that resistance to anti-EGFR therapy in HNSCC is probably not the result of hypoxic regions within the tumor and other mechanisms are involved.

【 授权许可】

   
2015 Boeckx et al.

【 图 表 】

Figure1.

Figure2.

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